Through its cancer drug screening program, Cytovia has discovered a natural product (CV2060) which potently induces caspase-mediated apoptosis in tumor cells derived from difficult-to-treat human cancers. The long-term objective of this grant is to advance CV2060 or an optimized analogue to clinical trials. This objective will be achieved by defining the molecular mechanism of action of CV2060, by producing analogues of CV2060 with improved chemical properties, and by establishing the efficacy of CV2060 and selected analogues in animal- cancer models. The mechanism of action will be defined by examining in detail the effect of CV2060 on apoptosis signal transduction and by isolating the CV2060 binding protein. The compound will be optimized by generating a library of over 400 analogues using conventional chemical synthesis and parallel synthesis. The in vivo efficacy will be determined using two different mouse xenograft models of human cancer (a hollow fiber model and a standard subcutaneous implant model). These experiments will provide the data necessary to bring CV2060 to the next stage of preclinical testing and, ultimately, to tests in human patients. CV2060 potentially represents a completely new drug treatment for cancer and therefore may address the enormous unmet need for innovative cancer therapies. PROPOSED COMMERCIAL APPLICATION: CV2060 is a novel natural product with the ability to induce apoptosis (programmed cell death) in human tumor cells. It is much more effective at killing cells derived from difficult-to-treat human cancers (such as breast and lung) than are anticancer drugs currently on the market. Therefore, CV2060 may represent a new class of anticancer agent with the potential to address the enormous unmet need for innovative cancer therapies.